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Integrating patient reported outcomes into clinical trials

How capturing the patient voice is unlocking medicines’ commercial potential


Patient-reported outcomes (PRO) are now critical to commercial success in many indications. 

Stung by products that failed to make a meaningful difference to people’s lives, payers and providers want to see evidence that therapies address the health problems patients face on a daily basis. Drug developers have responded by putting PROs at the heart of their clinical trial designs.

References to PROs in the academic literature date back to at least the 1950s but interest in the application of the tools in clinical trials only really gained momentum in the 1980s, when researchers began to worry outcomes traditionally used in oncology studies were ‘insensitive’ to psychosocial state, sociability and other measures beyond hard physical endpoints. That idea is now mainstream.

“It turns out that what is really bothering the patient and what is really bothering the doctor can be radically different things,” Janet Woodcock, director of the Center for Drug Evaluation and Research at the Food and Drug Administration, said in 2015.

“You have to start with an understanding of the impact of the disease on
the people who have it, and what they value most in terms of alleviation before you set up a measurement and go forward with truly patient- focused drug development.”

Woodcock’s views and the research that shaped them have contributed to quality of life, as captured by PRO measures, rising up the list of priorities at drug developers. In explaining how his company designs its R&D portfolio, Johnson & Johnson chief scientific officer Paul Stoffels said “quality of life is the first metric” on a 2019 conference call with investors.

Driving sales growth

Stoffels’ position benefits patients but is also indicative of the potential commercial impact of quality-of-life measures. The performance of Novartis’ heart failure drug Entresto offers one example of that potential.

In the two years up to May 2019, total US prescriptions of Entresto rose from below 15,000 to over 35,000. The increase has made Entresto a blockbuster. Sales in the second quarter of 2019 totalled $421m, up from $110m two years earlier.

Analysts at Jefferies said the rise was “likely driven by additional data generated on its quality- of-life benefits.” That conclusion reflects Novartis’ efforts to use PROs to show the effects of Entresto on quality-of-life measures.

For a registry study, Novartis asked patients to complete the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which tracks physical limitations, symptom frequency, social limitation and quality of life.

After around one month of treatment, 21.4% of patients on Entresto achieved large gains on KCCQ-12, compared to 12.5% in the control arm. Patients on Entresto reported particularly big improvements in the symptom frequency and quality of life domains, giving Novartis the data to support a message that has resonated with its customers.

“The quality-of-life data is probably one of the single biggest generators of interest,” Paul Hudson, the then-CEO of Novartis’ pharmaceuticals business, said on a conference call with investors in 2019.

Companies active across the therapeutic spectrum see PROs as key to their prospects. MyoKardia is gathering PROs in its phase 2 hypertrophic cardiomyopathy trial.

Aimmune Therapeutics prepared for commercialisation by using two PRO scales to show the effect of its peanut allergy drug on people’s emotions and social lives. Cara Therapeutics put two questionnaires about itching at the centre of its phase 3 pruritus trial. And Blueprint Medicines created a proprietary PRO for its mastocytosis drug.

Meeting stakeholder demands

The breadth of contexts in which PROs are collected points to some of the challenges faced by drug developers. For PROs to be effective, study sponsors need to pick a suitable scale and statistical plan.

Sponsors can choose from pan- disease PRO instruments, such as the EuroQoL-5 Dimensions (EQ-5D), and scales tailored to specific indications. Both have limitations. Pan- disease PROs may fail to capture the full effect of a drug, while indication-specific PROs prevent cross-disease comparisons.

Regulators have sought to help sponsors work PROs into trials, for example by publishing documents such as the European Medicines Agency guideline on PRO measures in oncology studies. However, there remains a disconnect between what sponsors are doing and what other stakeholders want.

That disconnect is evident in drug reviews published by health technology assessment (HTA) bodies, such as the United Kingdom’s National Institute for Health and Care Excellence (NICE). The reviews reveal recurring concerns with the PRO instruments used by sponsors.

NICE has favoured the use of the generic PRO EQ-5D since 2008 but is aware of the limitations of the measure. In its 2019 reviews of Pfizer’s Vizimpro and Takeda’s Adcetris, NICE noted that EQ-5D “may not be sensitive to skin-related diseases” and may fail to fully capture the effect of gastrointestinal dysfunction, for example by overlooking the impact of sweating and being repeatedly awoken in the night by irregular bowel movements.

HTA bodies are grappling with some of these limitations themselves. NICE, for example, has used a Dermatology Life Quality Index (DLQI) score of more than ten as a criterion for starting patients on psoriasis drugs for years.

However, the HTA acknowledges the limitations of the index, noting that “the DLQI has limited validity in some people, and may miss anxiety and depression.”

Developing new scales

Drug developers and HTAs persist with these imperfect PRO measures because of the lack of better alternatives.

Takeda, for example, used EQ- 5D in its Adcetris programme despite doubts about whether the measure was sensitive enough to show the therapy’s effect on cutaneous T-cell lymphoma (CTCL) symptoms such as the “constant severe, intense itching causing insomnia” that affects some patients. Despite the limitations, Takeda deemed EQ-5D to be one of its best PRO options.

However, those and other limitations are unlikely to last forever. Researchers are working on a CTCL PRO measure that could better capture what matters to patients with the disease. In other areas, drug developers themselves are helping to drive forward the field.

Blueprint Medicines is one company that took matters into its own hands. When Blueprint set out to develop avapritinib in systemic mastocytosis there was not a PRO measure for the rare disease, which causes a diverse range of symptoms such as itching, diarrhoea, joint pain and headaches.

That led Blueprint to work with healthcare value consultancy Adelphi Values to create a PRO measure.

The collaborators reviewed the literature and spoke to experts and patients to identify the most common symptoms. That effort led to a preliminary PRO measure that was refined by testing it with patients, following a questionnaire development practice known as cognitive debriefing, to ensure it was comprehensive and useable.

Designing PRO protocols

The choice of measure is just one of the critical decisions sponsors face when integrating PROs into their clinical trials. Sponsors also need to design a study protocol that includes information essential for the effective use of PROs. Multiple groups are involved in developing advice to help sponsors manage that task.

The activity has led to the development of the SPIRIT- PRO guidelines, which detail 16 items specific to PROs that should be included in protocols when patient-reported measures are used as primary or secondary endpoints.

The guidelines describe best practices such as stating specific PRO hypotheses, identifying the person responsible for the PRO portion of the trial and disclosing the required sample size. By meeting these minimum requirements, sponsors can increase the likelihood they will deploy PROs effectively.

At a time when quality-of-life measures are driving commercial outcomes, sponsors’ ability to design clinical trials that deploy PROs effectively can be a key competitive advantage.

Companies that gain that advantage stand to do more than just grow sales. They will also more consistently develop drugs that affect the outcomes that matter most to patients.

Nick Taylor is a journalist specialising in the life sciences industry

21st October 2019

Nick Taylor is a journalist specialising in the life sciences industry

21st October 2019

From: Research


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